Search

Introduction: The Cancer and Aging Research Group (CARG) prediction tool was designed in the United States to predict grade ≥ 3 chemotherapy-related adverse events (CRAE) in older patients. However, its usefulness among Japanese people, who have different sensitivities to anticancer drugs and life expectancy, remains unknown. We aimed to prospectively evaluate the utility of the CARG tool for predicting severe CRAE in older Japanese patients with cancer., Material and Methods: Patients with solid tumors aged 65 years and older who commenced anticancer drug regimens from April 2018 to October 2020 were divided into three groups (low, medium, and high-risk) based on their CARG risk scores. Toxicity was prospectively observed by a pharmacist. The primary objective was to evaluate the correlation between the incidence of grade ≥ 3 CRAE and the CARG risk score. The secondary objective was to evaluate hematological and non-hematological toxicities. CRAE incidence was compared among the three groups using a closed testing procedure: (1) Cochran-Armitage test for trend and (2) chi-square test for paired comparison., Results: The patients (N = 165) had a median age of 71 years (range: 65-89 years). CRAE in patients divided into low-, medium-, and high-risk groups, based on CARG risk scores, were 39%, 55%, and 82%, respectively (low vs high; p < 0.001, medium vs high; p < 0.01). The incidence of severe hematologic toxicity was 37%, 35%, and 50% in the low-, medium-, and high-risk groups, respectively; the incidence of severe non-hematologic toxicity was 15%, 36%, and 65%, respectively (low vs medium; p < 0.01, low vs high; p < 0.001, and medium vs high; p < 0.01)., Discussion: To our knowledge, this is the first prospective observational study to validate the CARG prediction tool in older Japanese patients with cancer. The CARG risk score may be effective in predicting the development of non-hematologic toxicities. These results should be considered when administering chemotherapy to older Japanese patients with advanced solid tumors., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cluster of differentiation (CD) 155 is a transmembrane protein that belongs to the nectin-like molecule family, which is widely overexpressed in several types of cancer. However, the clinical significance of CD155 in pathologic stage I lung adenocarcinoma remains poorly understood., Methods: We analyzed 320 patients diagnosed with pathologic stage I lung adenocarcinoma who underwent surgical treatment at Kyushu University Hospital between 2006 and 2015. The number of tumor cells expressing CD155 was assessed by immunohistochemistry, and patients were categorized into high and low CD155 expression groups. We compared the clinical and pathologic characteristics and clinical outcomes between these groups., Results: Mutation status of the epidermal growth factor receptor gene (EGFR) was determined in 237 patients. A total of 106 patients (33.1%) had EGFR wild-type, and 131 patients (40.9%) had EGFR mutant-type. CD155 expression was classified as high in 77 patients (24.1%) and as low in 243 (75.9%) as low. Multivariate analysis identified pleural invasion and EGFR wild-type as independent predictors of high CD155 expression. The Kaplan-Meier plot demonstrated significantly poorer recurrence-free survival and overall survival in the high CD155 group compared with the low CD155 group. Multivariate analysis showed high CD155 expression was an independent poor prognostic factor for recurrence-free and overall survival. Subgroup analyses revealed that a prognostic difference related to CD155 expression was observed only in patients with EGFR wild-type but not in those with EGFR mutant-type., Conclusions: Our findings suggest that high expression of CD155 is associated with EGFR wild-type and could serve as a valuable prognostic marker in pathologic stage I lung adenocarcinoma, particularly in cases without EGFR mutation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: High recurrence rate following curative surgery for non-small cell lung cancer (NSCLC) presents a major clinical challenge. Understanding the site and timing of recurrence and their impact on post-recurrence survival (PRS) is important for optimal postoperative surveillance and therapeutic intervention. In this study, we investigated the influence of the time to recurrence (TTR) and initial recurrence site on PRS., Materials and Methods: This multicentre prospective cohort study included patients who experienced recurrence after NSCLC resection between 2010 and 2015. The relationship between TTR and initial recurrence site, and their impact on PRS, was further evaluated. The hazard ratio (HR) for PRS was analysed using the Cox proportional hazards model., Results: Among 495 patients, the median TTR was 14 (range, 1-158) months; the mode of recurrence was 11 months. Early recurrence within 6 months was observed in 17 % of patients, and 68 % of patients showed recurrence within 2 years post-surgery. The HR for PRS was the highest in patients with a TTR within 6 months, and a noticeable decline was observed after the first 6 months. The HRs of TTRs beyond 2 years were not significantly different. The liver was a significantly unfavourable prognostic site for metastases (HR 2.2; P = 0.01), and metastases frequently recurred within 6 months after surgery. The timing of brain metastasis did not significantly impact the PRS., Conclusion: Earlier recurrence after surgery was associated with shorter PRS. In contrast, recurrences occurring >2 years after surgery do not significantly affect PRS., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Atezolizumab following platinum chemotherapy and complete pulmonary resection has become the new standard of adjuvant care for patients with stage II-III non-small cell lung cancer (NSCLC) expressing programmed death-ligand 1 (PD-L1). However, the efficacy and safety of postoperative adjuvant therapy and subsequent atezolizumab in patients aged 75 and older have not been established., Methods: Patients with completely resected stage II-III NSCLC aged 75 and older will be prospectively registered in this single-arm phase II study. The enrolled patients will receive cisplatin plus vinorelbine (CDDP + VNR) followed by atezolizumab for up to 12 months. PD-L1 expression in at least 1% of cells will be confirmed by immunohistochemical staining. We plan to enroll 33 patients over 1 year at 25 institutions in Japan. The primary endpoint is the completion rate of adjuvant treatment (CDDP + VNR initiation to atezolizumab completion)., Conclusion: The present study represents the first prospective trial of the tolerability of postoperative adjuvant therapy with immune checkpoint inhibitors in elderly individuals. The results of this trial might help promote postoperative adjuvant immunotherapy in the future for the elderly., Competing Interests: Disclosure Dr. Matsubara has received honoraria from Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical, AstraZeneca, Boehringer-Ingelheim, and MSD outside the submitted work. Dr. Yamaguchi reported grants from Chugai Pharmaceutical during the conduct of the study. Dr. Okamoto reported receiving grants from Chugai Pharmaceutical during the conduct of the study; grants from Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, MSD, Astellas, Novartis, and AbbVie; and personal fees from AstraZeneca, AbbVie, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Pfizer, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Novartis, and Chugai Pharmaceutical outside the submitted work. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Inc.)

Context: Antipsychotics are often used in managing symptoms of terminal delirium, but evidence is limited., Objectives: To explore the comparative effectiveness of haloperidol with as-needed benzodiazepines (HPD) vs. chlorpromazine (CPZ) vs. levomepromazine (LPZ) for agitated delirium in the last days., Methods: A prospective observational study was conducted in two palliative care units in Japan. Adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS-PAL) of one or more were included; palliative care specialist physicians determined that the etiology was irreversible; and estimated survival was 3 weeks or less. Patients treated with HPD, CPZ, or LPZ were analyzed. We measured RASS, NuDESC, Agitation Distress Scale (ADS), and Communication Capacity Scale (CCS) on Days 1 and 3., Results: A total of 277 patients were enrolled, and 214 were analyzed (112 in HPD, 50 in CPZ, and 52 in LPZ). In all groups, the mean RASS-PAL score significantly decreased on Day 3 (1.37 to -1.01, 1.87 to -1.04, 1.79 to -0.62, respectively; P < 0.001); the NuDESC and ADS scores also significantly decreased. The percentages of patients with moderate to severe agitation and those with full communication capacity on Day 3 were not significantly different. The treatments were well-tolerated. While one-fourth of HPD group changed antipsychotics, 88% or more of CPZ and LPZ groups continued the initial antipsychotics., Conclusion: Haloperidol with as-needed benzodiazepine, chlorpromazine, or levomepromazine may be effective and safe for terminal agitation. Chlorpromazine and levomepromazine may have an advantage of no need to change medications., Competing Interests: Disclosures The authors declare no financial relationships with commercial interests., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance., Methods: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity., Results: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs., Conclusions: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies have developed risk stratification schemas to assess systemic therapy toxicity. However, it is controversial which geriatric assessment variables should be used to assess the individual risk of severe treatment-associated toxicity in older adult patients., Materials and Methods: Patients aged ≥70 years with advanced non-small cell lung cancer (NSCLC) treated at 24 National Hospital Organization institutions completed a pre-first-line systemic therapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. Patients were followed through one cycle of systemic therapy to assess grade 3 (severe) to grade 5 (death) adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0., Results: In total, 348 advanced NSCLC patients with a median age of 76 years (range, 70 to 95 years) joined this prospective study. Severe adverse events ≥grade 3 occurred in 136 patients (39.1%). Predictors of hematologic toxicity were treatment variables, body mass index, body weight loss, and limitation in daily living due to dementia. These predictors provided the predictive model of hematologic toxicity ≥grade 3; 0 point (22.2%), 1 point (33.8%), 2 points (59.6%), ≥3 points (73.3%). Sex, daily living independence level, and lactate dehydrogenase levels were associated with non-hematologic toxicity ≥grade 3 in multivariate analysis. A scoring system using these predictors distinguished the risk levels of non-hematologic toxicity ≥grade 3; 0 point (6.6%), 1 point (12.2%), 2 points (39.0%), 3 points (75.0%)., Discussion: A stratification using individual extracted risk factors may be useful to predict the vulnerability to systemic therapy in older adult NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin., Materials and Methods: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan-Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching., Results: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test., Conclusion: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Osimertinib is a standard first-line treatment for non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR-tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance-associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R., Patients and Methods: A total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival., Conclusion: This is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood., Methods: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis., Results: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival., Conclusion: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to examine the efficacy and safety of gemcitabine plus nab-paclitaxel (GnP) in older patients with metastatic pancreatic cancer (MPC), especially those ≥75 years old., Materials and Methods: This study retrospectively enrolled 153 patients with MPC who received GnP as first-line chemotherapy. Patients ≥75 years old were allocated to the older group, and those <75 years old were assigned to the non-older group. We compared safety, antitumor efficacy, and survival between the two groups. In the older group, prognostic indicators of survival were also assessed., Results: The pretreatment characteristics of the two groups were not significantly different excluding age, history of malignancy, and C-reactive protein levels. The initial dose and relative dose intensities of GnP were significantly lower in the older group. There were no significant differences in the adverse event and antitumor response rates between the two groups. Median progression-free survival and overall survival were 5.5 and 12.0 months, respectively, in the older group, versus 6.0 and 11.1 months, respectively, in the non-older group. In the older group, a Geriatric Nutrition Risk Index (GNRI) of less than 86 was associated with poor prognosis., Conclusion: GnP exhibited acceptable efficacy and safety in patients ≥75 years old with MPC. GNRI might be helpful for identifying older individuals at higher risk of unfavorable outcomes., Competing Interests: Declaration of Competing Interest Yasunori Kawaguchi received a personal fee from Taiho Pharmaceutical; Mototsugu Shimokawa received a personal fee from Sysmex Corporation: Shiho Arima received personal fees from Taiho Pharmaceutical, Novartis Pharma, Chugai, Bristol-Myers Squibb, Daiichi-Sankyo, and AstraZeneca; Akitaka Makiyama received personal fees from Eli Lilly, Chugai, and Takeda; Tsuyoshi Shirakawa received consulting fees from Taiho Pharmaceutical, Chugai, and Takeda; and Taiga Otsuka received a grant from Chugai. The remaining authors have no competing interests or financial disclosures to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069)., Patients and Methods: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m 2 ] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%., Conclusion: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC., Competing Interests: Akira Hamada has received grants and personal fees from AstraZeneca, personal fees from Chugai, and grants from the Japan Society for the Promotion of Science. Junichi Soh has received grants from AstraZeneca, and grants from the Japan Society for the Promotion of Science. Akito Hata has received grants and personal fees from AstraZeneca, Eli Lilly, and Boehringer Ingelheim, personal fees from Chugai, and grants from MSD. Kiyoshi Nakamatsu has received grants from AstraZeneca. Yasushi Yatabe has received grants and personal fees from AstraZeneca, personal fees from MSD, Chugai-pharma, Pfizer, Roche/Ventana, Agilent/Dako, Thermo Fisher Science, ArcherCD, Novartis, Elli-Lily, and Daiichi Sankyo. Hiroyuki Oizumi has received grants from AstraZeneca and ONO Pharmaceutical Co., Ltd. Masahiro Tsuboi has received grants and personal fees from AstraZeneca, ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Eli Lilly Japan, MSD, and Novartis, and personal fees from Johnson and Johnson Japan, Chugai Pharmaceutical Co., Ltd., Teijin Pharma, Taiho Pharma, Medtronic Japan, and grants from Beohringer-Ingelheim Japan. Hidehito Horinouchi has received grants and personal fees from AstraZeneca, BMS, ONO, MSD, Janssen, and Chugai, personal fees from Lilly, Merck Biophama, Kyowa-Kirin, and Nihonkayaku, and grants from Daiichi-Sankyo, Abbvie, and Genomic Health. Ichiro Yoshino has received grants and personal fees from AstraZeneca. Masayuki Tanahashi has received grants from AstraZeneca. Shinichi Toyooka has received grants from AstraZeneca, Illumina, Eurofins, and Eli Lilly, grants and personal fees from Taiho, Kyorin, and Chugai, and personal fees from ONO, Daiichi-Sankyo, Medtronic, Johnson and Johnson. Morihito Okada has received grants and personal fees from AstraZeneca. Hiroyasu Yokomise has received grants from AstraZeneca. Motohiro Yamashita has received grants from AstraZeneca. Yasumasa Nishimura has received grants from AstraZeneca. Nobuyuki Yamamoto has received grants and personal fees from MSD K.K., AstraZeneca, ONO Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer-Ingelheim, Novartis, and Pfizer Inc., personal fees from Thermo Fisher Scientific, Bristol-Myers Squibb, Life Technologies Japan Ltd., Nippon Kayaku, and Merk Biopharma, and grants from Astellas Pharma Inc., Tsumura & Co., Shionogi Co., Ltd., AbbVie GK., Amgen Inc., Kyorin Pharmaceutical Co., Ltd., Eisai Co., Ltd., Terumo Corporation, Toppan Printing Co., Ltd., and Tosoh. Kazuhiko Nakagawa has received grants and personal fees from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bristol Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited, and AbbVie Inc, grants, personal fees, and other from Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Eli Lilly Japan K.K., and Takeda Pharmaceutical Co., Ltd., personal fees from Clinical Trial Co., Ltd., Medicus Shuppan, Publishers Co., Ltd., Care Net, Inc., Reno, Medical K.K., Medical Review Co., Ltd., Roche Diagnostics K.K., Bayer Yakuhin, Ltd., Medical Mobile Communications Co., Ltd., 3H Clinical Trial Inc., Nichi-Iko Pharmaceutical Co., Ltd., Nanzando Co., Ltd., Yodosha Co., Ltd., Nikkei Business Publications, Inc., Thermo Fisher Scientific K.K., Yomiuri Telecasting Corporation, and Nippon Kayaku Co., Ltd., personal fees and other from Kyorin Pharmaceutical Co., Ltd., and grants from inVentiv Health Japan, ICON Japan K.K., Gritsone Oncology, Inc., Parexel International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services Japan K.K., EP-CRSU Co., Ltd., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd, Bayer Yakuhin, Ltd., EPS International Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Tetsuya Mitsudomi has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Chugai, personal fees from Bristol-Myers Squibb, Eli Lilly, Merck Sharp and Dohme, and Pfizer, grants from Daiichi Sankyo, Taiho, Ono Pharmaceutical, and the Japan Society for the Promotion of Science, and other from Novartis. The other authors have stated that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: Small-for-size graft (SFSG) syndrome is a major cause of graft loss after living donor liver transplantation (LDLT). Splenectomy (Spx) is an option to prevent this catastrophic complication, but its effect remains controversial. Herein, we aimed to elucidate the effect of simultaneous Spx on graft function and long-term outcomes after LDLT., Methods: Three hundred and twenty patients were divided into 2 groups: those undergoing (n = 258) and those not undergoing (n = 62) simultaneous Spx. To overcome selection bias, propensity score matching (PSM) was performed (n = 50 in each group)., Results: Before PSM, recipients undergoing simultaneous Spx showed better graft function on post-operative day (POD) 7 and 14, as well as lower sepsis frequency within 6 months after LDLT and better graft survival rates compared to those not undergoing Spx. After PSM, compared to patients not undergoing Spx, those undergoing Spx had a lower frequency of early graft dysfunction on POD 7 (p = 0.04); a lower frequency of SFSG syndrome (p = 0.01), lower serum total bilirubin levels (p = 0.001), and lower international normalized ratio (p = 0.004) on POD 14; lower sepsis frequency within 6 months after LDLT (p = 0.02), and better graft survival rates (p = 0.04). Univariate analysis revealed that not undergoing Spx (hazard ratio 3.06; 95% CI 1.07-11.0; p = 0.037) was the only risk factor for graft loss after LDLT., Conclusions: Simultaneous Spx may prevent SFSG syndrome and is a predictive factor for graft survival after LDLT. Simultaneous Spx is recommended when a small graft (≤35% of standard liver weight) is predicted preoperatively, or for patients with portal hypertension or high portal pressure (above 20 mmHg) after reperfusion in LDLT., Lay Summary: Living donor liver transplantation (LDLT) for patients with acute or chronic liver failure is an alternative to overcome the deceased donor shortage. The potential mismatch between graft and body size is a problem that needs to be solved for LDLT recipients. Herein, we evaluated the impact of simultaneous splenectomy and showed that it was associated with favorable outcomes in patients undergoing LDLT., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (MS) is the most common long-term complication after liver transplantation, and it has been increasing in incidence. The aim of this study was to clarify the risk factors for each MS component -hypertension, diabetes mellitus, and dyslipidemia-after living-donor liver transplantation (LDLT), including characteristics of living-donors., Methods: Data related to clinicopathological parameters including MS components in 461 consecutive patients who underwent LDLT were analyzed retrospectively., Results: Prevalence of all MS components (hypertension, diabetes mellitus, and dyslipidemia) increased from 9.3%, 16.5%, and 7.2% before LDLT to 44.9%, 45.3%, and 50.8% after LDLT, respectively. By multivariate logistic regression analysis, the three factors, cyclosporine use (OR 2.086, P = 0.001), recipient age (OR 1.036, P = 0.001), and BMI (OR 1.072, P = 0.026) were independent predictors for post-LDLT hypertension. Next, the three factors, male recipient (OR 2.471, P < 0.001), recipient age (OR 1.039, P = 0.002), and donor BMI (OR 1.124, P = 0.012) were independent for post-LDLT diabetes mellitus. The four factors, cyclosporine use (OR 2.015, P = 0.001), prolonged prednisolone use (OR 1.928, P = 0.002), recipient age (OR 1.019, P = 0.037), and GRWR (OR 0.316, P = 0.037) were independent for post-LDLT dyslipidemia as well., Conclusions: Not only recipient-related factors but also donor-related factors were independently associated with each targeted post-LDLT MS component., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Preoperative skeletal muscle loss was reported to be associated with a postoperative poor prognosis in non-small cell lung cancer (NSCLC) patients. The aim of this study was to elucidate the relationship between the change in skeletal muscle mass after surgery and the postoperative outcomes in NSCLC patients., Methods: The data were analyzed for 204 NSCLC patients who had undergone curative lung resection and whose preoperative and postoperative (1-year) computed tomographic images were available. The skeletal muscle area (SMA) at the 12th thoracic vertebra level was used. Postoperative/preoperative ratio was defined as postoperative normalized SMA (cm 2 /m 2 ) divided by preoperative normalized SMA. The cutoff value was set to a postoperative/preoperative ratio of 0.9. The neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio, modified Glasgow prognostic score, and prognostic nutritional index were used to estimate change in the nutritional status., Results: There were 70 patients (34.3%) classified into the SMA-decreased group. Low body mass index was significantly associated with the SMA-decreased patients (P = .019). The SMA-decreased status was an independent prognostic factor for poor overall survival (P < .001) and disease-free survival (P = .001). The SMA-decreased status was significantly associated with the postoperative exacerbation of the neutrophil-lymphocyte ratio (P = .009), platelet-lymphocyte ratio (P = .026), modified Glasgow prognostic score (P = .003), and prognostic nutritional index (P = .013)., Conclusions: Skeletal muscle loss after surgery is significantly associated with poor postoperative outcomes in NSCLC patients. Further studies investigating the clinical impact of postoperative nutritional intervention are needed., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data., Patients and Methods: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model., Results: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively., Conclusion: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We investigated the utility of the clinical T factor of the 8th edition of the TNM classification, which newly defines the consolidation size of the tumor, as a valuable predictor of pathologic lymph node metastasis (pN+) and the prognosis., Methods: We retrospectively reviewed 825 patients with surgically resected cN0 M0 non-small cell lung cancer of any T stage, focusing on the tumor's total size (7th edition) and consolidation size (8th edition) and examined pN+ and the prognosis., Results: No pN+ cases in the 7th or 8th edition groups had a tumor size of less than 1 cm, and in those sized 1 to 3 cm, the frequency of pN+ in the 7th and 8th edition groups was 10.3% and 13.4%, respectively. The frequency of pN+ in tumors without ground glass opacity (GGO-) was 5.5-times higher than that of tumors with GGO (GGO+). The frequency of pN+ in the GGO+ 8th edition group was twice that in the GGO+ 7th edition group. The frequency of pN+ in the GGO- 7th edition group was 4-times higher than that of the GGO+ 7th edition group. A multivariate analysis revealed that total size exceeding 2 cm, consolidation size exceeding 2 cm, and GGO- were significant predictors of a pN+ status, indicating that a consolidation size of more than 2 cm was a stronger predictor than a total size of more than 2 cm., Conclusions: A consolidation size of more than 2 cm and GGO- were predictors of pN+, and the clinical T factor of the 8th Edition was a stronger predictor of the pN+ status than that of the 7th edition., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The epithelial-mesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with non-small-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma., Patients and Methods: We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching., Results: E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity score-matched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio = 2.57, P = .0451) and overall survival (hazard ratio = 4.23, P = .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival., Conclusion: The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Enhancer of zeste homolog 2 (EZH2) is reported to be involved in lung cancer pathogenesis via the epigenetic regulation of various genes. Recently, EZH2 was shown to control mechanisms of adaptive resistance to immunotherapy in melanoma; however, the association between EZH2 and programmed death-ligand 1 (PD-L1), which reflects the tumor microenvironment, remains poorly understood., Methods: A total of 428 patients with resected lung adenocarcinoma were analyzed for their EZH2 and PD-L1 expression by immunohistochemistry and evaluated to determine the association between the EZH2 and PD-L1 expression., Results: Among 428 patients, the EZH2 expression was identified in 219 (51.2%) patients, while the PD-L1 expression was observed in 88 (20.6%) patients. The recurrence-free and overall survival were significantly shorter in patients with the EZH2 expression than in those without it. A multivariate analysis showed that EZH2 remained an independent prognosticator for recurrence-free and overall survival. Patients with the EZH2-positive lung adenocarcinoma exhibited a significantly higher expression of PD-L1 than did those without it. A logistic regression analysis with backward elimination revealed that the presence of lymphatic and vessel invasion and PD-L1 positivity were independently associated with the EZH2 expression, while age over 70 years, the presence of vessel invasion, wild-type epidermal growth factor receptor, and EZH2 positivity were significantly associated with the PD-L1 expression., Conclusions: EZH2-expressing lung adenocarcinomas were shown to express the PD-L1 protein more frequently than were nonexpressing lesions. This study provides the first evidence of a possible association between the EZH2 and PD-L1 expression in patients with resected lung adenocarcinoma., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m 2 , day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Stroke is a major cause of morbidity or death after lung operations. Carotid artery screening (CAS) is useful for detecting carotid artery stenosis, which is one of the causes of stroke. This study investigated the frequency of and risk factors for preoperative carotid artery stenosis to determine whether CAS with ultrasonography contributes to preventing postoperative stroke or cardiovascular comorbidities in lung cancer patients., Methods: This retrospective study included 1,676 consecutive lung cancer patients who underwent surgical resection., Results: Of the 1,342 patients who underwent CAS, 173 (12.9%) had carotid artery stenosis. Significant associations with carotid artery stenosis were found for older patients (p < 0.0001), men (p < 0.0001), smoking history (p < 0.0001), history of stroke (p = 0.0037), cardiovascular diseases (p < 0.0001), hypertension (p = 0.0353), diabetes mellitus (p = 0.0037), and peripheral vascular diseases (p < 0.0001). Patients with the three independent risk factors of age, male sex, and history of cardiovascular diseases had a 6.43-fold higher prevalence of carotid artery stenosis (odds ratio, 6.43; 95% confidence interval, 3.80 to 10.89) than those with none of these factors. Propensity score-matched analysis showed that incidences of postoperative stroke and cardiovascular comorbidities were both lower in patients who underwent CAS and received appropriate anticoagulant therapy than in those who did not (p = 0.0619 and p = 0.0319, respectively)., Conclusions: Preoperative CAS is a simple and useful tool for detecting carotid artery stenosis. Administration of perioperative anticoagulant therapy to preoperative patients with lung cancer and carotid artery stenosis identified by CAS may prevent postoperative stroke and cardiovascular events., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Thymidine phosphorylase (TP) is a rate-limiting enzyme in thymidine catabolism. TP has several important roles in biological and pharmacological mechanisms; importantly TP acts as an angiogenic factor and one of metabolic enzymes of fluoro-pyrimidine anticancer agents and modifies inflammation. Improving our understanding of the characteristics and functions of TP has led to the development of novel TP-based anticancer therapies. We recently reported that TP-dependent thymidine catabolism contributes to tumour survival in low nutrient conditions and the pathway from thymidine to the glycolysis cascade is affected in the context of physiological and metabolic conditions. In this review, we describe recent advancement in our understanding of TP, with a focus on cancer cell biology and the pharmacology of pyrimidine analogue anticancer agents. This review provides comprehensive understanding of the molecular mechanism of TP function in cancer., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: The development of immune checkpoint inhibitors against programmed death 1 has paved the way for a new era of treatment of lung cancer. Programmed death-ligand 1 (PD-L1) is expected to predict the response of immune checkpoint inhibitors in lung cancer. Predicting PD-L1 expression using a noninvasive method before immunotherapy would, therefore, help identify patients for whom immunotherapy can be successful., Patients and Methods: A total of 394 patients with resected lung adenocarcinoma who had undergone preoperative thin-section computed tomography (CT) were analyzed for PD-L1 expression by immunohistochemistry and evaluated to determine the association between PD-L1 expression and CT characteristics, including convergence, surrounding ground glass opacity (GGO), air bronchogram, notching, pleural indentation, spiculation, and cavitation., Results: Of the 394 patients, 78 (19.8%) were positive and 316 (80.2%) were negative for PD-L1 expression. Univariate analysis demonstrated that PD-L1 + adenocarcinoma was significantly associated with the presence of convergence (P < .01), notching (P < .01), spiculation (P < .01), and cavitation (P < .01) and the absence of surrounding GGO (P < .01) compared with PD-L1 - cases. On multivariate analysis, the presence of convergence (P < .01) and cavitation (P < .01) and the absence of surrounding GGO (P = .02) and air bronchogram (P = .03) were significantly associated with PD-L1 expression., Conclusion: PD-L1 + adenocarcinoma cases showed convergence and cavitation more frequently than did PD-L1 - cases. In contrast, surrounding GGO and air bronchogram were observed less frequently in PD-L1 + cases than in PD-L1 - cases. These results will prove helpful in identifying PD-L1-expressing adenocarcinoma by CT before immunotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with anti-PD-1 therapy currently the standard treatment for non-small-cell lung cancer (NSCLC) patients after the failure of first-line chemotherapy treatment. The recent phase II POPLAR and phase III OAK studies showed that atezolizumab, a representative PD-L1 inhibitor, exhibited a survival benefit compared with standard therapy in patients with NSCLC., Patients and Methods: We examined PD-L1 expression in NSCLC using the clone SP142 of POPLAR and OAK studies. PD-L1 expression in 499 surgically resected NSCLC patients was evaluated using immunohistochemistry using SP142. We set cutoff values as 1%, 5%, 10%, and 50%., Results: The samples from 189 (37.9%), 119 (23.8%), 71 (14.2%), and 39 (7.8%) patients were positive for PD-L1 expression at cutoff values of 1%, 5%, 10%, and 50%, respectively. Fisher exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, advanced stage, the presence of vascular invasion, squamous cell carcinoma, and wild type epidermal growth factor receptor gene mutation status at all cutoff values. Univariate and multivariate survival analyses revealed that PD-L1-positive patients had a worse prognosis than PD-L1-negative patients only at the 1% cutoff value. Forest plot analyses showed that the 1% cutoff provided a more sensitive value for the prediction of postoperative prognosis., Conclusion: PD-L1 expression varied greatly according to different cutoff values. This study might be a useful reference to understand the results of POPLAR and OAK studies and to select patients likely to benefit from atezolizumab., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log 10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log 10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log 10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively ( P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively ( P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach., (© 2017 by The American Society of Hematology.)

Objectives: Despite the survival benefit and acceptable tolerability of eribulin for advanced/metastatic breast cancer (MBC) patients pretreated with anthracyclines and taxanes, there is limited evidence of the clinical benefit of early eribulin use. We investigated the efficacy and safety of first- to third-line eribulin use in patients with MBC., Materials and Methods: In this phase II, open-label, single-arm study conducted at 14 sites in Kyushu, Japan, women with histologically confirmed human epidermal growth factor receptor 2-negative MBC were enrolled between December 1, 2011 and November 30, 2013 (Data cut-off: November 30, 2014). Objective response rate (ORR; primary endpoint), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety were evaluated., Results: Of 53 recruited patients, 47 were enrolled. The ORR was 17.0% (95% confidence interval, 7.6-30.8), DCR was 66.0% (51.2-77.8), median PFS was 4.9 months (3.5-7.0), DOR was 6.6 months (1.9-14.3), and median OS was 17.4 months (10.1-not evaluable). The common grade 3/4 adverse events were neutropenia (25 patients; 53.2%), leucopenia (16 patients; 42.1%) and febrile neutropenia (4 patients; 8.5%). Toxicity did not increase during the long-term treatment. Subgroup analysis indicated that first-line treatment led to higher ORR and prolonged PFS and OS than second-/third-line treatment and that incidence of adverse events in patients of second-/third-line treatment was not higher than that in patients of first-line treatment., Conclusion: Eribulin exhibited efficacy and manageable tolerability in Japanese women with pretreated MBC in first- to third-line use. (ID: UMIN000007121)., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The clinicopathological features of carcinomas expressing programmed death ligand 1 (PD-L1) and their associations with common driver mutations, such as mutations in the EGFR gene, in lung adenocarcinoma are not clearly understood. Here, we examined PD-L1 protein expression in surgically resected primary lung adenocarcinoma and the association of PD-L1 protein expression with clinicopathological features, EGFR mutation status, and patient outcomes., Methods: The expression of PD-L1 protein in 417 surgically resected primary lung adenocarcinomas was evaluated by immunohistochemical analysis. The cutoff value for defining PD-L1 positivity was determined according to the histogram of proportions of PD-L1-positive cancer cells., Results: Samples from 85 patients (20.4%) and 144 patients (34.5%) were positive for PD-L1 protein expression according to 5% and 1% PD-L1 cutoff values, respectively. Fisher's exact tests showed that PD-L1 positivity was significantly associated with male sex, smoking, higher tumor grade, advanced T status, advanced N status, advanced stage, the presence of pleural and vessel invasions, micropapillary or solid predominant histological subtypes, and wild-type EGFR. Univariate and multivariate survival analyses revealed that patients with PD-L1 positivity had poorer prognoses than those without PD-L1 protein expression at the 1% cutoff value (disease-free survival p < 0.0001, overall survival p < 0.0001)., Conclusions: PD-L1 protein expression was significantly higher in smoking-associated adenocarcinoma and in EGFR mutation-negative adenocarcinoma. PD-L1 protein expression was associated with poor survival in patients with lung adenocarcinoma. The PD-L1/programmed cell death 1 pathway may contribute to the progression of smoking-associated tumors in lung adenocarcinoma., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected., (© 2015 by The American Society of Hematology.)

Introduction: Virtual touch tissue quantification (VTTQ) has been developed to evaluate tissue elasticity. Our previous study using delivered placentas showed increased elasticity in fetal growth restriction (FGR). Therefore, we investigated changes in placental elasticity during pregnancy, including complicated pregnancies., Methods: Based on complications, 199 women were divided into 5 groups (normal, FGR, pregnancy induced hypertension (PIH), diabetes mellitus and collagen disease), and shear wave velocity (SWV) of the placenta, measured using VTTQ, was compared. A cross-sectional study was performed with the 143 normal cases to construct the reference range. The association between placental SWV and the expression ratio of collagen fibers in the placenta stained with Masson's trichrome was determined., Results: The SWV was safely measured for all participants. The correlation between SWV and gestational weeks was not significant. The mean ± SD SWVs in the normal, FGR, and PIH groups were 0.98 ± 0.21, 1.28 ± 0.39, and 1.60 ± 0.45 m/sec, respectively. The FGR and PIH groups had significantly higher SWVs than that of the normal group. SWV and the expression ratio of collagen fibers were significantly correlated., Discussion: Based on the present findings, changes in SWV during pregnancy were associated with placental fibrosis, and increased SWV in PIH and/or FGR cases might be influenced by infarction, ischemic changes, and inflammation, as well as fibrosis. In conclusion, the measurement of placental SWV is potentially useful to evaluate the condition of the placenta during pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The velocities of the lateral shear waves (Vs; m s⁻¹) generated by an acoustic radiation force impulse (ARFI) correlate with Young's modulus. Therefore, ARFI can be used as a new method to evaluate tissue elasticity. The aim of this study was to investigate the safety of ARFI imaging and the differences in placental elasticity in complicated cases., Methods: The study population included 115 patients between 26 and 41 weeks gestation, who were divided into three groups, namely normal, fetal growth restriction (FGR) and pregnancy-induced hypertension (PIH). After delivery, the Vs values of the placenta were measured ex vivo. After ARFI imaging, microscopic examination was performed, the Vs values were compared among the three groups and the relationship between the Vs values and neonatal birthweight Z-score was investigated., Results: No histological changes were noted even after ARFI imaging. The Vs values in the FGR group were significantly higher than those in the normal group (1.94 ± 0.74 and 1.31 ± 0.35 m s⁻¹, respectively; p < 0.05). The Vs values demonstrated a significant negative correlation with the Z-score. Moreover, as the Z-score became lower, the Vs values became higher in the range of Z-scores under -0.5 standard deviation (SD)., Discussion: We speculate that the increased Vs values in the FGR group may have been caused by histological changes, and that a more severe FGR might result in increased Vs values., Conclusion: ARFI imaging was observed to have no apparent histological damage to the placental tissue. Ex vivo placentas from the FGR group were significantly more firm. Moreover, Vs values and Z-scores of birthweight had a significant negative correlation. Additional investigations are needed about the utility of this method for the evaluation of placental function in vivo., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Cutaneous spindle cell squamous cell carcinoma (SCC) is a rare, but highly malignant variant of SCC. The presence of spindle-shaped cells with a sarcomatous appearance, which are derived from squamous cells, suggests that these cells are produced as a result of epithelial-mesenchymal transition (EMT). EMT is a complex process in which epithelial cells lose their polarity and cell-cell contacts, while also acquiring increased motility and invasiveness. Snail regulates EMT by binding to proximal E-boxes in the promoter region of E-cadherin and repressing its transcription. When examining the expression of EMT markers and Snail in spindle cell SCCs, we found that cyclooxygenase-2 (COX-2) expression was down-regulated. Since it has been shown that COX-2 is constitutively overexpressed in a variety of malignancies, including colon, gastric, and lung carcinomas, the down-regulation of COX-2 expression was unexpected. The presence of E-box-like sequences in the promoter region of COX-2 prompted us to perform a more detailed analysis. We introduced a Snail expression vector into keratinocyte-derived cell lines (HaKaT, HSC5, and A431 cells), and isolated stable transfectants. We determined that COX-2 expression was down-regulated in cells expressing Snail. Consistent with these observations, reporter assays revealed that COX-2 promoter activity was repressed upon Snail overexpression. Thus Snail down-regulates COX-2 in these cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In an attempt to enhance the immunological efficacy of genetic immunization, we investigated a new biological means for delivering antigen gene directly to the cytoplasm via membrane fusion. In this context, we investigated fusogenic liposome (FL) encapsulating DNA as a possible genetic immunization vehicle. RT-PCR analysis indicated that a FL could introduce and express encapsulating OVA gene efficiently and rapidly in vitro. Consistent with this observation, an in vitro assay showed that FL-mediated antigen-gene delivery can induce potent presentation of antigen via the MHC class I-dependent pathway. Accordingly, immunization with FL containing the OVA-gene induced potent OVA-specific Th1 and Th2 cytokine production. Additionally, OVA-specific CTL responses and antibody production were also observed in systemic compartments including the spleen, upon immunization with the OVA-gene encapsulating FL. These findings suggest that FL is an effective genetic immunization carrier system for the stimulation of antigen-specific immune responses against its encoding antigen.

We previously reported the development of chicken monoclonal antibodies (mAb) against mammalian-conserved molecules by cell fusion and phage display using the mouse mAb expression vector pPDS. However, chicken hybridomas produce relatively small amounts of antibody when compared with mouse hybridomas, and application of the pPDS may be limited in two-antibody assays with a mouse mAb because it contains mouse Ckappa as a detection tag. To circumvent the above problems, two expression vectors were established and used to produce a functional recombinant chicken mAb. These vectors, which were designed to accommodate a single chain fragment of the variable region (scFv) of the antibody, contained a chicken Clambda and FLAG with or without 6 x histidine sequences in the 3' terminus of the scFv to serve as detection and purification tags. In this study, a prion protein (PrP)-specific chicken mAb (HUC2-13) was expressed as phage-displayed and soluble scFv mAb forms by using these vectors. The scFv mAbs expressed by these vectors exhibited the same antigen-binding specificity to PrP as that of the original HUC2-13, could be purified with ease, and used in combination with a mouse mAb. These results indicate that the methods described herein offer an alternative to chicken mAb production from hybridomas and immunized chicken splenocytes, and may contribute to the use of chicken mAb reagents in numerous fields.

Pathological expression of myotonic'dystrophy protein kinase (DMPK) in skeletal muscle of myotonic dystrophy (DM) was studied by Western blot analysis, immunohistochemistry, and immunoelectron microscopy of DMPK. Western blot analysis showed that DMPK protein in DM skeletal muscles dramatically decreased. DMPK-positive muscle fibers showed typical DM pathological changes such as type I atrophy, central nuclei, nuclear chains, and sarcoplasmic masses. In degenerated DMPK-positive muscle fibers, cross-striated bands disappeared, and irregular granular DMPK-positive materials appeared in sarcoplasm. By immunoelectron microscopy, DMPK was localized in the terminal cisternae of the sarcoplasmic reticulum (SR) in DM muscle. Swollen DMPK-positive SRs were detected between well preserved myofibrils in the early stage of DM muscle degeneration, and degenerated intramembranous structures with DMPK and an accumulation of mitochondria were observed between disorganized myofibrils in degenerated DM muscle. We concluded that SR is the primary site of the degeneration of DM skeletal muscle and that the decreased DMPK might cause dysregulation of intracellular calcium metabolism, which is followed by DM muscle degeneration.

It is quite important to know the exact localization and function of myotonin protein kinase (MtPK), identified as the gene product of myotonic dystrophy, the most prevalent disease with multisystem disorders among muscular dystrophies. To investigate the localization of MtPK, we raised a polyclonal antibody against a synthetic peptide chosen within the deduced sequence of MtPK. This antibody detected both a membrane-bound 70-kd protein and a soluble 55-kd protein on Western blots of human muscles. By using this antibody for immunohistochemical studies of both biopsied human skeletal muscle fibers and mature innervated cultured muscle fibers, we can now demonstrate by confocal laser scanning microscopy that MtPK is localized mainly in the I-band. By immunoelectron microscopy, it was determined that MtPK is a membrane-bound protein localized mainly in the terminal cisternae of the sarcoplasmic reticulum. To our knowledge, this is the first documentation of the ultrastructural localization of MtPK. This finding is quite important for clarifying the pathophysiological basis of myotonic dystrophy, which might be due to a dysregulation of calcium metabolism.

Although the etiology of Alzheimer's disease has not been elucidated yet, dysfunction and loss of synapses are believed to cause dementia. Recent studies suggest that the primary cause of the disease is closely related to the aberrant processing of the amyloid precursor protein (APP). To investigate the localization of APP at synaptic sites, we obtained synaptic plasma membrane and synaptic vesicles from rat brain. Enhanced chemiluminescence (ECL) western blot analysis using two specific polyclonal antibodies against APP revealed strong APP immunoreactivity in the synaptic plasma membrane, but not in the synaptic vesicle fraction. These data indicate that APP is localized at the synaptic plasma membrane and may play a role in physiological synaptic activity. Alternative localization or aberrant processing of APP at the synaptic site may cause impairment of synaptic function in Alzheimer's disease.

A simple, selective, sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of amfenac sodium (AMF) and its metabolite (7-benzoyl-2-oxindole, S1) in plasma was established. To 100 microliters of plasma, purified water (100 microliters), ammonium sulphate (0.2 g) and ethanol (100 microliters) containing fenbufen (100 micrograms/ml, internal standard) were added. After centrifugation the ethanol layer was directly injected into a reversed-phase ODS column. AMF and S1 were eluted using a gradient buffer system of 20-80% acetonitrile-phosphate buffer (pH 7.0), and detected at 245 nm. The analytical recoveries of AMF at concentrations of 0.5, 2 and 10 micrograms/ml in plasma were ca. 92.1, 95.4 and 94.6%, respectively. The coefficients of variation of the AMF recoveries were below 4.6%. The S1 recoveries at the concentrations of 40, 200 and 400.ng/ml were ca. 93.4, 98.7 and 95.3%, and the coefficients of variation were below 6.0%. The coefficients of variation for intra- and inter-day variation of AMF (5 micrograms/ml) and S1 (100 ng/ml) were 4.5 and 3.6% and 4.2 and 4.2%, respectively. The detection limits of AMF and S1 in plasma were as low as 0.1 microgram/ml and 20 ng/ml, and the coefficients of variation were 4.0 and 4.4%, respectively. The method was applied to determine the plasma concentrations of AMF and S1 after oral administration of AMF capsules (100 mg of AMF) to human volunteers.